Opioids Flashcards
How does nociceptive pain occur?
- Stimulation of nociceptors afferent fibres (Aδ, C) by initiating mediators (H+, K+, ACh, 5HT, Histamine) and sensitising mediators (Prostaglandin, Leukotrienes, Neurokinin)
What are Aδ fibres?
Small myelinated
Conduct sharp pain rapidly
What are C fibres?
Unmyelinated
Conduct dull pain slowly
Enter dorsal horn & synapse
Substantia gelatinosa integrate inputs
How do opioids inhibit pain?
- Bind to inhibitory G-proteins
- Voltage-sensitive Ca2+ Channels close
- Hyperpolarization by K+ efflux
- Adenylase cyclase inhibition
- Reduced cAMP
- Inhibit transmission between nerves
Where are µ receptors and what do they do?
- Throughout CNS, primary afferents in dorsal horn
- Resp depression (reduce chemoreceptor sensitivity to CO2)
- Constipation (reduce secretions & peristalsis)
- CV depression
What is Morphine?
Naturally occurring Phenanthrene derivative
µ- receptor agonist
What are the effects of Morphine?
- Effective for visceral pain
- Histamine release & bronchospasm
- 5HT & dopamine stimulating = vomiting
- Pruritis marked following epidural/intrathecal
- Meiosis (Edinger-Westphal nucleus)
- Inhibits prolactin, ACTH, GnT
- Inc ureteric tone & retention
How is morphine absorbed?
- Ionised in gastric acidity
- Absorption delayed until reaches small bowel (alkaline) = unionised
- Undergoes 1st-pass metabolism to morphine-3-glucuronide
- Conc in brain falls slowly due to low lipid solubility
What is diamorphine?
Diacetylated morphine derivative
No affinity for opioid receptors
Prodrug
How is diamorphine absorbed?
- High lipid solubility, well absorbed from gut
- Low PO bioavailability due to high 1st-pass
- Metabolised in liver, plasma, CNS by ester hydrolysis
How is Codeine absorbed?
- Due to methyl group reduced 1st pass metabolism
- Eliminated by 1 of 3 liver pathways
1) 6-hydroxyglucoronidation
2) N-demethylation
3) O-demethylation (depends on CYP2D6)
What is Fentanyl?
Synthetic phenylpiperidine derivative
Rapid onset
µ-receptor agonist
Why does an epidural Fentanyl bolus not cause resp depression?
High lipid solubility
Rapidly diffuses out of CSF into spinal cord
How is Fentanyl absorbed?
- High lipid solubility = rapid onset
- Short duration of action due to distribution
- Can become trapped in the stomach where 99% ionised
- Passes into alkaline s.bowel for absorption
- Rapid hepatic 1st-pass (N-demethylated)
What are Pethidine, Remi & Alfentanil?
Synthetic phenylpiperidine derivative
µ-receptor agonist
How is Alfentanil absorbed?
- 89% in unionised form, able to cross lipid membranes
- Faster onset of action
- Metabolised by N-demethylation
What drugs can increase the 1/2 life of Alfentanil?
- Midazolam: Also metabolised by CYP3A3/4)
- Erythromycin: Inhibits CYP450
How is Remi absorbed?
- Duration of action determined by metabolism NOT distribution
- Rapidly broken down by non-specific plasma & tissue esterases
What drug group should Pethidine NOT be given with?
MAOIs
Central serotoninergic hyperactivity
Coma, seizure, hyperpyrexia, labile circulation
How is Pethidine absorbed?
- More lipid soluble than morphine
- Metabolised by liver ester hydrolysis
- Metabolite derivative = renal failure, hallucinations, seizures
What is the MOA of Methadone?
- Opioid antagonist
- NMDA receptor antagonist - Tx certain neuropathic pain resistant to opioids
What is Tramadol?
Cyclohexanol derivative
What is the MOA of Tramadol?
- Agonist of all opioid receptors ( particularly µ)
- Inhibits reuptake of NorA & 5HT
- Stimulates presynaptic 5HT release
What is a contraindication to Tramadol
Epilepsy
How is Tramadol absorbed?
High oral bioavailability
- Metabolised by hepatic CPY2D6, CYP3A4, CYP2B6
What receptors dose Naloxone work at?
µ, δ, κ
Highest affinity to µ
